Abstract

BackgroundMalaria remains a serious health problem because resistance develops to all currently used drugs when their parasite targets mutate. Novel antimalarial drug targets are urgently needed to reduce global morbidity and mortality. Our prior results suggested that inhibiting erythrocyte Gs signaling blocked invasion by the human malaria parasite Plasmodium falciparum. Methods and FindingsWe investigated the erythrocyte guanine nucleotide regulatory protein Gs as a novel antimalarial target. Erythrocyte “ghosts” loaded with a Gs peptide designed to block Gs interaction with its receptors, were blocked in β-adrenergic agonist-induced signaling. This finding directly demonstrates that erythrocyte Gs is functional and that propranolol, an antagonist of G protein–coupled β-adrenergic receptors, dampens Gs activity in erythrocytes. We subsequently used the ghost system to directly link inhibition of host Gs to parasite entry. In addition, we discovered that ghosts loaded with the peptide were inhibited in intracellular parasite maturation. Propranolol also inhibited blood-stage parasite growth, as did other β2-antagonists. β-blocker growth inhibition appeared to be due to delay in the terminal schizont stage. When used in combination with existing antimalarials in cell culture, propranolol reduced the 50% and 90% inhibitory concentrations for existing drugs against P. falciparum by 5- to 10-fold and was also effective in reducing drug dose in animal models of infection.ConclusionsTogether these data establish that, in addition to invasion, erythrocyte G protein signaling is needed for intracellular parasite proliferation and thus may present a novel antimalarial target. The results provide proof of the concept that erythrocyte Gs antagonism offers a novel strategy to fight infection and that it has potential to be used to develop combination therapies with existing antimalarials.

Highlights

  • Plasmodium falciparum is a protozoan parasite that causes the most lethal form of malaria, a major human disease urgently in need of new targets for future antimalarial drugs

  • When used in combination with existing antimalarials in cell culture, propranolol reduced the 50% and 90% inhibitory concentrations for existing drugs against P. falciparum by 5- to 10-fold and was effective in reducing drug dose in animal models of infection. Together these data establish that, in addition to invasion, erythrocyte G protein signaling is needed for intracellular parasite proliferation and may present a novel antimalarial target

  • The results provide proof of the concept that erythrocyte Gs antagonism offers a novel strategy to fight infection and that it has potential to be used to develop combination therapies with existing antimalarials

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Summary

Introduction

Plasmodium falciparum is a protozoan parasite that causes the most lethal form of malaria, a major human disease urgently in need of new targets for future antimalarial drugs. During P. falciparum blood-stage infection, the extracellular merozoite adheres to erythrocytes, and invades and develops intracellularly, surrounded by a parasitophorous vacuolar membrane. One strategy for developing new drugs is termed the ‘‘host-targeted’’ approach This means that rather than trying to block processes occurring within the parasite itself, a drug can be developed which blocks processes within the person’s red blood cells, and which would otherwise be needed for the parasite to complete its life cycle. It will be difficult for malaria parasites to evolve resistance to such a drug, because changes in a person’s red blood cells occur much more slowly than in the parasites themselves

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